Autodigestion

Abstract

There is currently no effective treatment for multiorgan failure following shock other than alleviation supportive care. A better understanding of the pathogenesis of these sequelae to shock is required. The intestine plays a central role in multiorgan failure. It was previously suggested that bacteria and their toxins are responsible for the organ failure seen in circulatory shock, but clinical trials in septic patients have not confirmed this hypothesis. Instead, we review here evidence that the digestive enzymes, synthesized in the pancreas and discharged into the small intestine as requirement for normal digestion, may play a role in multi-organ failure. These powerful enzymes are non-specific, highly concentrated and fully activated in the lumen of the intestine. During normal digestion they are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier. However, if this barrier becomes permeable, e.g. in an ischemic state, the digestive enzymes escape into the wall of the intestine. They digest tissues in the mucosa and generate small molecular weight cytotoxic fragments such as unbound free fatty acids. Digestive enzymes may also escape into the systemic circulation and activate other degrading proteases. These proteases have the ability to clip the ectodomain of surface receptors and compromise their function; for example cleaving the insulin receptor causing insulin resistance. The combination of digestive enzymes and cytotoxic fragments leaking into the central circulation causes cell and organ dysfunction, and ultimately may lead to complete organ failure and death. We summarize current evidence suggesting that enteral blockade of digestive enzymes inside the lumen of the intestine may serve to reduce acute cell and organ damage and improve survival in experimental shock.

Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock

“…These circulating mediators may include digestive pancreatic proteases 15 and products of proteolysis that either directly, 27 or indirectly through vasoactive degradation products 14 affect receptor function, and thus vascular responsiveness. Supporting this hypothesis are our current findings that enteral TXA restores receptor levels to baseline concentrations with commensurate improvements in hemodynamics in experimental hemorrhagic shock by protecting the ischemic small bowel from proteolytic degradation; 11, 12, 15 this protection is not seen with intravenous protease inhibitor treatment. 28 …”

“…We hypothesize that decreased transmembrane receptor density in shock may result, either directly or indirectly, from uncontrolled proteolytic activity, possibly by digestive pancreatic enzymes from the small intestine. 11 Integrity of the intestinal mucous layer is compromised in circulatory shock, 12–14 and a consequence of the breakdown of this barrier may be leakage of digestive enzymes and inflammatory products from the intestinal lumen into the bloodstream. 15 Once in the systemic circulation, these mediators may lead to remote organ failure and mortality (autodigestion).…”

“…15 Once in the systemic circulation, these mediators may lead to remote organ failure and mortality (autodigestion). 11 …”

Complement in Pancreatic Disease—Perpetrator or Savior?

“…In the systemic circulation, these pancreas-derived proteases may cleave off cellular surface molecules and receptors and activate other proteases (24, 25), such as coagulation, fibrinolytic, and complement factors. The resulting “autodigestion” and dysregulation of important innate immune cascades reflect main pathophysiological features of MODS.…”

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

“…However, it is clear that hydrolytic enzymes released by leukocytes, such as collagenase, elastase and matrix metalloproteinase-9, degrade important structural components of the endothelial glycocalyx, basement membrane, and ECM, thereby contributing to leukocyte-dependent microvascular barrier dysfunction in postischemic tissues (Altshuler, Kistler & Schmid-Schonbein, 2016; Carden & Korthuis, 1996; Granger & Korthuis, 1995; Kalogeris et al, 2012, 2016; Schmid-Schonbein, 2016). …”